PROJECT SUMMARY/ABSTRACT Genetic data have the potential to improve the care of patients with the common colorectal disease diverticulitis. Every year over 200,000 people are hospitalized with diverticulitis in the United States. Attacks of diverticulitis are characterized by abdominal pain, fevers, chills, and gastrointestinal distress. For most patients, attacks are mild and self-limited, but 10-35% go on to suffer severe disease: multiple hospitalizations, colon perforation, and abdominal sepsis. Tens of thousands of patients undergo major surgery every year to prevent severe disease. Currently, however, surgeons have no ability to predict which patients will have severe disease. There is an unmet clinical need for improved understanding of the disease and risk stratification. Historically, diverticulitis was considered an environmental disease related to diet, but data show clear evidence of heritability; 40-53% of individual risk of diverticulitis is due to genetics. My preliminary work described the genomic architecture of diverticulitis and identified 42 genetic loci associated with the disease. This proposal builds on that preliminary work to further investigate the genetic contribution to diverticular disease. My central hypothesis is that genetic risk factors can predict severity of diverticulitis, interact with modifiable risk factors ? such as visceral adiposity, and may manifest themselves as diverticulitis or as other clinically-associated connective tissue traits including hernia, prolapse, and aneurysm. The overall goal of this application is to support my training and development as an independent investigator in genomic epidemiology. The career development plan includes completion of a master?s degree in bioinformatics, structured mentorship, and enhancement of skills through performance of research. My main research goal is to determine how a patient?s genetic background influences the development and course of diverticular disease. The major themes of this project are reflect in the Specific Aims: 1) Generate and validate a polygenic risk score for severe diverticulitis using four large biobanks, 2) Incorporate polygenic and morphometric data to improve diverticulitis risk stratification by assessing the interaction of visceral adiposity and genetic risk, 3) Investigate a common genetic causality for diverticular disease as a composite connective tissue degenerative trait, examining an underlying genetic basis for phenotypes clinically linked to diverticulitis. Successful completion of these studies will enhance our understanding of the role of genetics in diverticulitis, lead to further large scale prospective research, and translate into meaningful genomic tools for patients with diverticulitis.